P1028: PTG-300 (RUSFERTIDE) TREATMENT INTERRUPTION REVERSES HEMATOLOGICAL GAINS AND RESTORES THERAPEUTIC BENEFIT ON REINITIATION IN SUBJECTS WITH POLYCYTHEMIA VERA
Authors: A. Kuykendall, M. Kremyanskaya, Y. Ginsburg, N. Pemmaraju, E. Ritchie, J. Gotlib, F. Valone, S. Khanna, S. Gupta, R. Hoffman, S. Verstovsek
Journal: HemaSphere (2022)

Background: Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) and if needed, cytoreductive therapy to maintain hematocrit (HCT) <45% to reduce the incidence of thrombosis. Constitutive erythropoiesis and repeated TP result in iron deficiency which further stimulates iron absorption and availability for robust erythropoiesis. Iron deficiency contributes to fatigue, which is the most severe and prevalent symptom for patients with PV. We have previously shown that adding Rusfertide, a hepcidin mimetic, to existing PV treatment, significantly, and effectively reverses iron deficiency and essentially eliminates TP requirement for >1 year in PV patients [Hoffman ASH 2021]. The ongoing PTG-300-04 (NCT04057040) Phase 2 study of Rusfertide in TP-dependent PV patients experienced an FDA-mandated brief hold which resulted in dosing interruption of Rusfertide for all patients. Aims: To examine the impact of temporary rusfertide withdrawal on iron homeostasis and TP requirements after temporary suspension in the ongoing PTG-300-04 study. Methods: Eligibility criteria for PTG-300-04 study include PV diagnosis [by 2016 WHO criteria] and ≥3 phlebotomies with/without concurrent cytoreductive therapy in the 24 weeks before enrollment. Rusfertide 10-120 mg weekly SQ injection was added to existing cytoreductive treatment and adjusted to maintain HCT <45%. During the brief clinical hold patients were maintained on their cytoreductive regimens and had TP for HCT >45%. Most patients returned to Rusfertide add-on treatment 2-3 months after the dosing interruption and reinititation. Results: Pre-enrollment, PV patients were treated with TP alone (30) or with TP+cytoreductive therapy (33). TP requirements in the 24 weeks before enrollment ranged from 3 to 9. Rusfertide treatment enabled consistent HCT control <45%, essentially eliminated TPs in all sub-groups, decreasing RBC count and increased MCV and MCH values. Pre-enrollment, mean iron-related parameters were consistent with systemic iron deficiency. Rusfertide treatment resulted in progressive normalization of serum ferritin, suggesting a redistribution of systemic iron. During Rusfertide dosing interruption, all patients had significant (p<0.01) increase in TPs, HCT, and RBC count; and a simultaneous decrease in MCV and serum ferritin. Patients also reported increase in PV-related symptoms (i.e., increased fatigue and worsening concentration). Reinitiating Rusfertide resulted in rapid normalization of hematologic parameters, elimination of TP, and improvement in symptoms demonstrating potential effectiveness of this approach. Most adverse events were grade 1-2. The most frequent AE was transient injection site reaction reported in 59% of patients. Summary/Conclusion: The current results support Rusfertide as an effective treatment option in PV, reversing iron deficiency and essentially eliminating TP requirements in PV patients with/without cytoreductive agents. Reversal of hematological parameters during dosing interruption further confirms the effect of Rusfertide on both iron homeostasis and erythrocytosis. Taken together, Rusfertide is a very promising novel biologic agent in both low and high-risk PV patients. A global Phase 3 trial of rusfertide in PV, VERIFY, has been initiated.